Pharmaceuticals which enhance neurotransmission of serotonin (5-HT) are useful for the treatment of many psychiatric disorders, including depression and anxiety. The first generation of non-selective serotonin-affecting drugs operated through a variety of physiological means which caused them to possess numerous undesired side-effects. The more recently prescribed drugs, the selective serotonin reuptake inhibitors (SSRIs), act predominately by inhibiting 5-HT, which is released at the synapses, from being actively removed from the synaptic cleft via a presynaptic serotonin transport carrier. Since SSRIs require several weeks before they exert their full therapeutic effect, this 5-HT blockade mechanism cannot fully account for their therapeutic activity. It is speculated that this two week induction which occurs before a full antidepressant effect is observed, is due to the involvement of the 5-HTlA autoreceptors which suppress the firing activity of 5-HT neurons, causing a dampening of the therapeutic effect. Studies suggest that after several weeks of SSRI administration, a desensitization of the 5-HT autoreceptors occurs allowing a full antidepressant effect in most patients. (See, e.g., Le Poul et al., Arch. Pharmacol., 352:141 (1995)). Hence, it is believed that overriding this negative feedback by using 5HT1A antagonists would potentially increase and accelerate the clinical antidepressant response. Recent studies by Artigas et al., Trends Neurosci., 19:378-383 (1996), suggest a combination of 5-HT1A activity and inhibition of 5-HT uptake within a single molecular entity can achieve a more robust and fast-acting antidepressant effect.
The present invention relates to a new class of molecules which have the ability to act at the 5-HT1A autoreceptors and concommitantly with the 5-HT transporter. Such compounds are therefore potentially useful for the treatment of depression as well as other serotonin disorders.
U.S. Pat. No. 5,468,767 reports a series of substituted indoles of the following formula for the treatment of disorders associated with dysfunction in serotonergic neurotransmission, including depression ##STR2##
wherein:
R.sub.1 is hydrogen or C.sub.1-4 alkyl and R.sub.2 is C.sub.1-4 alkyl or (CH.sub.2)pAr. PA1 R is hydrogen or alkyl; PA1 R.sub.1 and R.sub.2 are each mono- or bicyclic aryl or heteroaryl radicals; PA1 R.sub.3 is hydrogen, alkyl, or a spirocycloalkyl group; and PA1 n is 1 or 2 and m is 1 to 3. PA1 R.sub.1, R.sub.2 and R.sub.3 are each, independently, hydrogen, halogen, CF.sub.3, alkyl, alkoxy, MeSO.sub.2, or together can form a 5-7 membered carbocyclic or heterocyclic ring; PA1 R.sub.4 is hydrogen, halogen, or alkyl; PA1 R.sub.5 is hydrogen, alkyl, alkylaryl, or aryl; PA1 R.sub.6 is hydrogen, halogen, CF.sub.3, CN, carbamide, or alkoxy; PA1 X.sub.1, X.sub.2 and X.sub.3 are each carbon or one of X.sub.1, X.sub.2 or X.sub.3 may be nitrogen; PA1 Y is carbon or nitrogen; and PA1 Z is carbon or nitrogen; or PA1 R.sub.4 is hydrogen or halogen; PA1 R.sub.5 is hydrogen, alkyl or alkylaryl; and PA1 R.sub.6 is hydrogen, halogen, CN or alkoxy; PA1 X.sub.1, X.sub.2, X.sub.3, Y and Z are each carbon; or PA1 3-[cis-4-[4-(1H-Indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole; PA1 3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole; PA1 4-Fluoro-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole; PA1 4-Fluoro-3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole; PA1 5-Fluoro-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole; PA1 5-Fluoro-3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole; PA1 6-Fluoro-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole; PA1 6-Fluoro-3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole; PA1 5-Bromo-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole; PA1 5-Bromo-3-[trans-4-[4-(1 H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1 H-indole; PA1 5-Chloro-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole; PA1 5-Chloro-3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole; PA1 3-{4-[(1,4-cis)-4-(1H-indol-4-yl)-piperazinyl-1-yl]cyclohexyl}-1H-indole-5- carbonitrile; PA1 3-{4-[(1,4-trans)-4-(1H-indol-4-yl)-piperazinyl-1-yl]cyclohexyl}-1H-indole- 5-carbonitrile; PA1 5-Methoxy-3-[cis-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole; PA1 5-Methoxy-3-[trans-4-[4-(1H-indol-4-yl)-1-piperazinyl]cyclohexyl]-1H-indole ; PA1 3-[cis-4-[4-(1H-Indol-4-yl)-1-piperazinyl]cyclohexyl]-2-methyl-1H-indole; PA1 3-[trans-4-[4-(1H-Indol-4-yl)-1-piperazinyl]cyclohexyl]-2-methyl-1H-indole; PA1 3-{(1,4-cis)-4-[4-1H-Indole-4-yl)-piperazin-1-yl]-cyclohexyl}-1H-pyrrolo[2, 3-b]pyridine; PA1 3-{(1,4-trans)-4-[4-(1H-Indol-4-yl)-piperazin-1-yl]-cyclohexyl}-1H-pyrrolo[ 2,3-b]pyridine; PA1 6-Fluoro-1-methyl-3-{cis-4-[4-(1-methyl-1H-indol-4-yl)-1-piperazinyl]cycloh exyl}-1H-indole; PA1 3-{(1,4-cis)-4-[4-(1H-indol-4-yl)-piperazin-1-yl]cyclohexyl}-1-methyl-1H-in dole-5-carbonitrile; PA1 3-{(1,4-trans)-4-[4-(1H-indol-4-yl)-piperazin-1-yl]cyclohexyl}-1-methyl-1H- 5-carbonitrile; PA1 1-Ethyl-3-{(1,4-cis)-4-[4-(1H-indole-4-yl)-piperazin-1-yl]-cyclohexyl}-1H-i ndole-5-carbonitrile; PA1 3-{(1,4-cis)-4-[4-(1H-indol-4-yl)-piperazin-1-yl]-cyclohexyl}-1-propyl-1H-i ndole-5-carbonitrile; PA1 3-{(1,4-trans)-4-[4-(1H-indol-4-yl)-piperazin-1-yl]-cyclohexyl; }-1-propyl-1H-indole-5-carbonitrile; PA1 3-{(1,4-cis)-4-[4-(1H-indol-4-yl)-piperazin-1-yl]-cyclohexyl}-1-isopropyl-1 H-indole-5-carbonitrile; PA1 3-{(1,4-trans)-4-[4-(1 H-indol-4-yl)-piperazin-1-yl]cyclohexyl}-1-isopropyl-1H-indole-5-carbonitr ile; PA1 1-Benzyl-3-{(1,4-cis)-4-[4-(1H-indol-4-yl)-piperazin-1-yl]-cyclohexyl}-1H-i ndole-5-carbonitrile; PA1 1-Benzyl-3-{(1,4-trans)-4-[4-(1H-indole-4-yl)-piperazin-1-yl]cyclohexyl}-1H -indole-5-carbonitrile; PA1 1-Methyl-3-{(1,4-cis)-4-[4-(1-methyl-1H-indol-4-yl)-piperazine-1-yl]-cycloh exl}-1H-indole-5-carbonitrile; PA1 5-Fluoro-3-{(cis)-4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-cyclohexyl}-1H-in dole; PA1 5-Fluoro-3-{(1,4-cis)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-cyclohexyl}-1 H-indole; PA1 5-Fluoro-3-{(1,4-trans)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-cyclohexyl} -1H-indole; PA1 5-methoxy-3-{(1,4-cis)-4-[4-(2-methoxy-phenyl)-piperazinyl-1-yl]-cyclohexyl }-1H-indole; PA1 5-Methoxy-3-{(1,4-trans)-4-[4-(2-methoxy-phenyl)-piperidin-1-yl]-cyclohexyl }-1H-indole; PA1 3-{(1,4-cis)-4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-cyclohexyl}-1H-pyrrolo [2,3-b]piperidine; PA1 5-Fluoro-3-{(cis)-4-[4-(5-fluoro-2-methoxy-phenyl)-piperazin-1-yl]-cyclohex yl}-1H-indole; PA1 5-Fluoro-3-{(trans)-4-[4-(5-fluoro-2-methoxy-phenyl)-piperazin-1-yl]-cycloh exyl}-1H-indole; PA1 3-{(1,4-cis)-4-[4[(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-cyclo hexyl}-4-fluoro-1H-indole; PA1 3-{(1,4-trans)-4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-cyc lohexyl}-4-fluoro-1H-indole; PA1 3-{(1,4-cis)-4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-cyclo hexyl}-5-fluoro-1H-indole; PA1 3-{(1,4-trans)-4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-cyc lohexyl}-5-fluoro-1H-indole; PA1 3-{(1,4-cis)-4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-cyclo hexyl}-6-fluoro-1H-indole; PA1 3-{(1,4-trans)-4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-cyc lohexyl}-6-fluoro-1H-indole; PA1 3-{(1,4-trans)-4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-cyc lohexyl}-6-fluoro-1H-indole; PA1 3-{(1,4-cis)-4-[4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-cyclo hexyl}-1H-indole-5-carbonitrile; PA1 3-{(1,4-trans)-4-(4-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-cyc lohexyl}-1H-indole-5-carbonitrile; PA1 8-{4-[(1,4-cis)-4-(5-Fluoro-1H-indol-3-yl)-cyclohexyl]-piperazin-1-yl}quino line; PA1 8-{4-[(1,4-trans)-4-(5-Fluoro-1H-indol-3-yl)-cyclohexyl]-piperazin-1-yl}-qu inoline; PA1 8-{4-(1,4-cis)-4-[4-(5-Fluoro-1-methyl-1H-indol-3-yl)-cyclohexyl]-piperazin -1-quinoline; PA1 3-[(1,4-cis)-4-(4-Quinolin-8-yl-piperazin-1-yl)-cyclohexyl]-1H-indole-5-car bonitrile; PA1 3-[(1,4-trans)-4-(4-Quinolin-8-yl-piperazin-1-yl)-cyclohexyl]-1H-indole-5-c arbonitrile; PA1 1-Methyl-3-[(1,4-cis)-4-(4-quinolin-8-yl-piperazin-1-yl)-cyclohexyl]-1H-ind ole-5-carbonitrile; PA1 5-Fluoro-3-{(1,4-cis)-4-[4-(6-fluoro-chroman-8-yl)-piperazin-1-yl]-cyclohex yl}-1H-indole; PA1 5-Fluoro-3-{(1,4-trans)-4-[4-(6-fluoro-chroman-8-yl)-piperazin-1-yl]-cycloh exyl}-1H-indole; PA1 5-Fluoro-3-{(1,4-cis)-4-[4-(5-fluoro-2,3-dihydro-benzofuran-7-yl)-piperazin -1-yl]-cyclohexyl}-1H-indole; PA1 5-Fluoro-3-{(1,4-trans)-4-[4-(5-fluoro-2,3-dihydro-benzofuran-7-yl)-piperaz in-1-yl]-cyclohexyl}-1H-indole; PA1 3-{(1,4-cis)-4-[4-(5-Fluoro-2,3-dihydro-benzofuran-7-yl)-piperazin-1-yl]-cy clohexyl}-1H-indole-5-carbonitrile; PA1 3-{(1,4-trans)-4-[4-(5-Fluoro-2,3-dihydro-benzofuran-7-yl)-piperazin-1-yl]- cyclohexyl}-1H-indole-5-carbonitrile; PA1 3-{(1,4-cis)-4-[4-(5-Fluoro-2,3-dihydro-benzofuran-7-yl)-piperazin-1-yl]-cy clohexyl}-1-methyl-1H-indole-5-carbonitrile; PA1 3-[(1,4-cis)-4-[4-(Benzofuran-7-yl-piperazin-1-yl)-cyclohexyl]-1H-indole-5- carbonitrile; PA1 3-[(1,4-trans)-4-[4-(Benzofuran-7-yl-piperazin-1-yl)-cyclohexyl]-1H-indole- 5-carbonitrile; PA1 5-Fluoro-3-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]cyclohex-1-enyl}-1H-indo le; PA1 3-{4-[4-(1H-Indol-4-yl)-piperazin-1-yl]-cyclohex-1-enyl}-1H-indole-5-carbon itrile; PA1 5-Fluoro-3-{(1,4-cis)-4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-cyclohexyl}-1 ,3-dihydro-indol-2-one; PA1 5-Fluoro-3-{cis-4-[4-(1H-indol-4-yl)piperazinyl]-cyclohexyl}-1-methyl-1H-in dole; PA1 8{(1,4-cis)-4-[4-(5-Fluoro-1H-indol-3-yl)-cyclohexyl]-piperazin-1-yl}-6-met hoxy-quinoline; PA1 8-{(1,4-trans)-4-[4-(5-Fluoro-1H-indol-3-yl)-cyclohexyl]piperazin-1-yl}-6-m ethoxy-quinoline; PA1 3-{(1,4-cis)-4-[4-6-Methoxy-quinoline-8-yl)-piperazin-1-yl]-cyclohexyl}-1H- indole-5-carbonitrile; PA1 3-{(1,4-trans)-4-[4-(6-Methoxy-quinolin-8-yl)-piperazin-1-yl]-cyclohexyl}-1 H-indole-5-carbonitrile; PA1 6-Chloro-8-{4-[1,4-cis)-4-(5-fluoro-1H-indol-3-yl)-cyclohexyl]-piperazin-1- yl}quinoline; PA1 6-Chloro-8-{4-[(1,4-trans)-4-(5-fluoro-1H-indol-3-yl)-cyclohexyl]-piperazin -1-yl}quinoline; PA1 3-{(1,4-cis)-4-[(4-(6-Chloro-quinolin-8-yl)-piperazin-1-yl]-cyclohexyl}-1H- indole-5-carbonitrile; PA1 3-{(1,4-trans)-4-[4-(6-Chloro-quinolin-8-yl)-piperazin-1-yl]-cyclohexyl}-1H -indole-5-carbonitrile; PA1 5-Chloro-8-{4-[(1,4-cis)-4-(5-fluoro-1H-indol-3-yl)-cyclohexyl]-piperazin-q uinoline; PA1 3-{(1,4-cis)-4-[4-(5-Chloro-quinolin-8-yl)-piperazin-1-yl]-cyclohexyl}-1H-i ndole-5-carbonitrile; PA1 5-Fluoro-8-{4-[(1,4-cis)-4-(6-fluoro-1H-indole-3-yl)-cyclohexyl]-piperazin- 1-yl}-quinoline; PA1 5-Fluoro-8-{4-[(1,4-trans)-4-(6-fluoro-1H-indol-3-yl)-cyclohexyl]-piperazin -1-yl}-quinoline; PA1 3-{(1,4-cis)-4-[4-(2-Methyl-quinolin-8-yl)-piperazin-1-yl]-cyclohexyl}-1H-i ndole-5-carbonitrile; PA1 3-{(1,4-trans)-4-[4-(2-Methyl-quinolin-8-yl)-piperazin-1-yl]-cyclohexyl}-1H -indole-5-carbonitrile; PA1 4-{4-[(1,4-cis)-4-(5-Fluoro-1H-indol-3-yl)-cyclohexyl]-piperazin-1-yl}-2-tr ifluoromethyl-quinoline; PA1 4-{4-[(1,4-trans)-4-(5-Fluoro-1H-indol-3-yl)-cyclohexyl]-piperazin-1-yl}-2- trifluoromethyl-quinoline; PA1 3-{(1,4-cis)-4-[4-(2-Trifluoromethyl-quinolin-4-yl)-piperazin-1-yl]-cyclohe xyl }-1H-indole-5-carbonitrile PA1 3-{(1,4-trans)-4-[4-(2-Trifluoromethyl-quinolin-4-yl)-piperazin-1-yl]-cyclo hexyl}-1H-indole-5-carbonitrile; PA1 4-{4-[(1,4-cis)-4-(5-Fluoro-1H-indol-3-yl)-cyclohexyl]-piperazin-1-yl}-6-me thoxy-quinoline; PA1 4-{4[(1,4-trans)-4-(5-Fluoro-1H-indol-3-yl)-cyclohexyl]-piperazin-1-yl}-6-m ethoxy-quinoline; PA1 3-{(1,4-cis)-4-[4-(6-Methoxy-quinolin-4-yl)-piperazin-1-yl]-cyclohexyl}-1H- indole-5-carbonitrile; and PA1 3-{(1,4-trans)-4-[4-(6-Methoxy-quinolin-4-yl)-piperazin-1-yl]-cyclohexyl}-1 H-indole-5-carbonitrile.
WO 9415928 discloses a series of piperazine derivatives of the following formula for the treatment of CNS disorders, including depression. ##STR3##
wherein:
WO 93/10092 discloses a series of cyclohexenes of the following formula for the treatment of dopaminergic disorders. ##STR4##